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Oct 30, 2007

Three Independent Studies Find Molecule Essential for EGFR Inhibitor-Induced Tumor Necrosis

  • Three independant papers published  on October 30 in PLoS Medicine describes work on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-induced tumor necrosis. All three show that BIM, a proapoptotic BH3-only protein also known as BCL2-like 11, is essential for the tumor-killing effects of drugs such as gefitinib and erlotinibin in EGFR mutated cancers.

    One of the studies was conducted by researchers at Harvard Medical School, University Hospitals of Cleveland, Case Western Reserve University, and Yale University School of Medicine. They report finding that BIM is involved in TKI-induced apoptosis and that the T790M and L747S mutations are linked to reduced expression of BIM and resistance to gefitinib.

    The second study was performed by investigators at the Memorial Sloan-Kettering Cancer Center. Using lung cancer cell lines they discovered that erlotinib icnreases BIM levels in sensitive but not in resistant cancer cell lines. The team says that they also found that RNAi-induced inhibition of BIM eliminated the effects of the drug. These results were verified in lung tumors and xenografts from mice bearing mutant EGFR-dependent lung adenocarcinomas, according to the researchers.

    Scientists at The Walter and Eliza Hall Institute of Medical Research produced the third paper, which also found that BIM is essential for the apoptotic effects of gefitinib in non-small-cell lung cancer (NSCLC). They further report that shutdown of the EGFR–MEK–ERK (mitogen-activated protein kinase kinase–extracellular signal-regulated protein kinase) signaling cascade is critical for BIM activation and that the addition of a BH3 mimetic significantly enhances killing of NSCLC cells by gefitinib.



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